Methods that provide for early and accurate detection of disease conditions are of great interest for clinical practice, however certain conditions, including systemic inflammatory conditions, may reach an advanced state before diagnosis is possible. These conditions can result from an interaction between a pathogenic microorganism and the host's defense system, which triggers the host inflammatory response. The complexity of the host's response during the systemic inflammatory response has complicated efforts towards understanding disease pathogenesis.
Bacteremia and sepsis are closely related conditions. Bacteremia denotes bacteria in the bloodstream. Sepsis refers to a serious infection, localized, bacteremic or due to fungal infections, that is accompanied by systemic manifestations of inflammation. Septic shock is sepsis with hypoperfusion and hypotension refractory to fluid therapy. The more general term, systemic inflammatory response syndrome, recognizes that several severe conditions, including infections, pancreatitis, burns, trauma, etc. can trigger an acute inflammatory reaction, the systemic manifestations of which are associated with release into the bloodstream of a large number of endogenous mediators of inflammation.
Transient bacteremia may be caused by surgical manipulation of infected oral tissues or even routine dental manipulations; catheterization of an infected lower urinary tract; incision and drainage of an abscess; and colonization of indwelling devices, especially IV and intracardiac catheters, urethral catheters, and ostomy devices and tubes; and the like. Gram-negative bacteremia is typically intermittent and opportunistic; although it may have no effect on a healthy person, it can be seriously important in immunocompromised patients with debilitating underlying diseases, after chemotherapy, and in settings of malnutrition.
When bacteremia or infections with certain fungi produce changes in circulation such that tissue perfusion is critically reduced, septic shock ensues. Septic shock is most common with infections by gram-negative organisms, staphylococci, or meningococci. Septic shock is characterized by acute circulatory failure, usually with or followed by hypotension, and multiorgan failure.
The pathogenesis of septic shock is not completely understood. The bacterial toxins generated by the infecting organisms trigger complex immunologic reactions: a large number of mediators, including tumor necrosis factor, leukotrienes, lipoxygenase, histamine, bradykinin, serotonin, and interleukin-2, have been implicated in addition to endotoxin.
Initially, vasodilation of arteries and arterioles occurs. Later, cardiac output may decrease and peripheral resistance may increase. Decreased organ perfusion particularly affects the kidneys and brain, and subsequently causes failure of one or more of the visceral organs. Ultimately, cardiac output declines and the typical features of shock appear. At the onset of septic shock, the leukocyte count may be significantly reduced, and the polymorphonuclear leukocytes (PMNs) may be as low as 20%. However, this situation rapidly reverses within 1 to 4 h, and a significant increase in both the total WBC count and PMNs usually occurs.
The difficulty in early diagnosis of sepsis is reflected by the high morbidity and mortality associated with the disease. Overall mortality in patients with septic shock ranges from 25 to 90%, and poor results often follow failure to institute therapy soon enough. However, experimental trials of therapy with monoclonal antibodies to the lipid A fraction of the endotoxin, antileukotrienes, and antibodies to tumor necrosis factor have been unsuccessful. Glucocorticoids are now of no routine benefit, although they may have a place in selected types of infection, such as meningitis, and in patients with adrenal insufficiency.
A need, therefore, exists for a method of diagnosing sepsis sufficiently early to allow effective intervention and prevention. There is a further need for the development of effective treatment for sepsis. The present invention addresses these needs.